Compositions for adhesion prevention

ABSTRACT

Compositions and methods for the prevention of adhesion development involve the administration of therapeutic formulations of a halogenated organic compound to a patient in need of treatment. The formulations can include suitable carriers for optimal administration.

BACKGROUND OF THE INVENTION

[0001] It is well known that postoperative adhesions develop in themajority of patients following surgery. Adhesions can result in seriousmedical consequences and lifelong morbidity, including infertility,abdomino-pelvic pain, small bowel obstruction, and difficult reoperativeprocedures. Adhesions can manifest themselves shortly after the surgicalprocedure is performed, or many years thereafter, without any degree ofpredictability. Although adhesions are common in intraabdominalsurgeries, adhesions can be a problem in virtually all types ofsurgeries. The haloorganic compounds of this invention, when formulatedinto pharmaceutical compositions, are useful in preventing or reducingthe development of postoperative surgical adhesions, and therefore areof major clinical significance for the reduction of patient morbidityand mortality.

[0002] Postoperative surgical adhesions are generally believed to resultfrom an injury or inflammation in the peritoneal cavity which produces afibrous exudate. As a result of this exudate, the serosal tissuesurfaces stick together. The fibrous exudate may be absorbed or invadedby fibroblasts to form a permanent fibrous adhesion.

[0003] Removal of fibrin before it is invaded by fibroblasts can preventthe development of permanent fibrous adhesions. Removal of fibrin occursdue to the fibrinolytic activity of the peritoneal cavity. Fibrinolyticactivity can vary as a result of surgery, but it is absent from aperitoneal wound during the first 48 hours following surgery. However,there is a gradual increase in fibrinolytic activity after this time forup to eight (8) days when the peritoneum heals.

[0004] The mechanisms of peritoneal healing, and the alterations whichresult in postoperative adhesion development, are not well understood.Compositions which are currently approved by the U.S. FDA for use in thereduction of intraperitoneal adhesions theoretically serve as adhesionbarriers that separate opposing, potentially adherable sites during thecritical three to five day period of peritoneal repair.

[0005] Such compositions, including Intercede™, which is manufacturedand sold by Johnson and Johnson, and Seprafilm™, which is manufacturedand sold by Genzyme Corporation, are resorbable. i.e. reabsorbed in thesurrounding tissue, and have been shown in clinical trials to reduceadhesions at the site where they are placed during a laparotomy.However, there is no clinical evidence that these compositions are ofany benefit at sites within the patient removed form the site ofapplication for the reduction of de novo adhesion formation, or for thereduction in adhesion reformation at such other sites. Similarly, thereis no convincing clinical evidence that these materials are efficaciousfor surgical procedures performed by laproscopy, perhaps in part due tothe difficulty in laproscopic placement of the material.

[0006] PCT published patent application WO 00/20642, published Apr. 13,2000, discloses methods for the prevention of adhesion development bythe administration of therapeutic formulations containing TIMP-1antibodies to a patient. TIMP-1 is part of a family of inhibitors ofmetalloproteinase proteins, or TIMP's, which regulate the catalyticactivity of matrix metalloproteinases (MMP's). The administration ofantibodies to TIMP-1 to a patient is believed to alter the local levelsof both TIMP-1 and MMP, and specifically to reduce the expression ofTIMP-1, to thereby inhibit the development of adhesions.

[0007] Accordingly, there is perceived to be a need for an improvedmethod for adhesion control and prevention which can be convenientlyadministered to a patient, and which is not restricted to the site of aparticular surgical procedure. There is a particular need for such an,improved method which can also be used in connection with the rapidlygrowing field of laproscopic surgeries, and at sites throughout the bodyin addition to the abdominal cavity.

SUMMARY OF THE INVENTION

[0008] The present invention relates to methods for preventing orreducing the development of surgical adhesions, and compositions whichcan be used in such methods.

[0009] In one aspect, the invention includes a pharmaceuticalformulation for preventing or reducing the development of surgicaladhesions. The formulation contains, as an active ingredient, ahalogenated organic compound of formula CR₁OOR₂, wherein R, is an alkylgroup of 1 to 4 carbons, or a haloalkyl group of 1 to 4 carbons, andwherein R₂ is selected from the group consisting of hydrogen, halogen,lower alkyl and lower haloalkyl, provided that either R₁ or R₂ mustcontain at least one halogen. The pharmaceutical formulation can alsoinclude suitable pharmaceutically acceptable carriers and adjuvants, aswell as other therapeutic compounds which assist in the prevention ofadhesions. The term “pharmaceutically acceptable carrier” denotes acarrier substance that potentiates, and does not significantly diminish,the effect of the active agent in the body.

[0010] The terms “prevent” and “preventing” as used herein refer toinhibiting completely or partially a biological response, as well asinhibiting an increase in a biological response. For instance,prevention of adhesion development refers to partially or completelyinhibiting adhesion formation and adhesion reformation, as well asinhibiting an increase in adhesion formation and adhesion reformation.

[0011] In a preferred embodiment, the halogenated compound of thisinvention is a halogenated acetic acid derivative, more preferablydichloroacetic acid or 2-chloropropionate. Prodrugs which form thehalogenated compounds in the body can also be used, and are includedwithin the scope of this invention. Additional modifications embraced bythis invention include carriers which can be used to bind thehalogenated compounds prior to administration, and which subsequentlyrelease the halogenated compounds in the body in active form. Suitablebiocompatible carriers are well known to those skilled in the art.

[0012] Typically, the pharmaceutical composition of the inventioncontains from about 1% to about 50% active ingredient, and preferablyfrom about 2% to about 10% active ingredient. Human dosages in the rangeof from about 10 mg/kg to about 100 mg/kg can be used depending on theseverity of the particular condition and the treatment protocol.

[0013] The pharmaceutical composition can be delivered to the subject byany route known in the art. For instance, the pharmaceutical compositioncan be administered systemically, such as orally or parenterally, or itmay be administered locally. The pharmaceutical composition can also bedelivered in a sustained release device. Alternatively, thepharmaceutical composition can be administered with an anti-adhesionadjuvant to obtain the benefits of a barrier compound and the adhesionprevention composition. The adjuvant may be used in the form of a gel,liquid or a solid membrane. Typical anti-adhesion adjuvants which areuseful in this invention include commercial products such as Intercede®and Seprafilm®.

[0014] In another aspect, this invention includes a method forpreventing or reducing the development of surgical adhesions by treatinga patient at risk of developing such adhesions with a therapeuticformulation containing, as an active ingredient, a halogenated organiccompound of formula CR₁OOR₂, wherein R₁ is selected from the groupconsisting of lower alkyl groups (of 1 to 4 carbons), or lower haloalkylgroups, and wherein R₂ is selected from the group consisting ofhydrogen, halogen, lower alkyl and lower haloalkyl, provided that eitherR₁ or R₂ must contain at least one halogen atom.

[0015] Although it is most common to use the pharmaceutical compositionsof this invention for peritoneal surgery, the type of surgery in whichthe product is used may be any type where there is a risk of developingsurgical adhesions associated with the surgery. In some embodiments, thesubject can undergo a surgery selected from the group consisting ofabdominal surgery, gynecological surgery, cardiac surgery, back surgery,neurosurgery, ligament and tendon surgery, and ophthalmic surgery.

DETAILED DESCRIPTION OF THE INVENTION

[0016] This invention is based, in part, on the discovery that thedevelopment of adhesions is a response mechanism by the subject to adisruption in the preexisting vasculature supplying blood to the injuredtissue present in the subject. Adhesions essentially represent amechanism for resupplying oxygen nutrients to the injured tissue topromote healing.

[0017] Tissue which is injured as a result of a pathological process, orby a surgical procedure undertaken to treat a pathology, experience adisruption in the vasculature, resulting in the delivery of less oxygenand nutrients to the tissue. This, in turn, causes a buildup ofmetabolic wastes due to the impairment of the normal mechanisms of wasteremoval.

[0018] Tissue normally utilize an aerobic metabolism in which energy isderived by the cells from the oxidation of metabolic intermediates andoxygen to form carbon dioxide. This metabolic reaction is the primaryroute by which cells are able to derive the maximum number of ATP(energy) molecules possible by passing all carbon sources beingmetabolized from pyruvate through the Kreb's (tricarboxylic acid) cycle.However, if the amount of oxygen is limited by the disruption of thevasculature delivering blood to the injured tissue, oxidative metabolismis hindered or rendered unable to occur. Such injury may be due, forinstance, to a pathological process, to the cutting of blood vessels, totying off vessels during surgery, or to the use of electrosurgicalenergy for sealing blood vessels. In such situations, the injured tissueproduces markedly fewer ATP molecules. In addition, pyruvate is lesslikely to enter the Kreb's cycle, but rather is converted into lacticacid which will build up in the affected, anoxic (hypoxic) tissues.

[0019] It is hypothesized that the body is able to sense theanoxia/hypoxia in the injured tissues, and in response, producesadhesions from adjacent tissue which subsequently become vascularized asa mechanism for resupplying oxygen and other nutrients to the tissue.This results in the attachment of tissues at non-physiologic locations,with the potential of untoward adverse clinical consequences.

[0020] While not intending to be bound by any particular theory, it isbelieved that the pharmaceutical compositions of this invention areeffective in reducing the incidence of post-operative adhesions bystimulating the activity of the enzyme pyruvate dehydrogenase, so thatvirtually all pyruvate enters the Kreb's cycle. This results in maximalATP production, while simultaneously reducing the conversion of pyruvateinto lactic acid. The tissue thus becomes less anoxic/hypoxic, and thereis less stimulus to form an adhesion. The pharmaceutical formulation isadvantageously administered to a subject prior to or during surgery, inorder to be present during the peritoneal healing, and preferably forapproximately three to five days following surgery.

[0021] The halogenated organic compounds of this invention includecompounds of the general formula CR₁OOR₂, wherein R₁ is selected fromthe group consisting of lower alkyl groups or lower haloalkyl groups,and wherein R₂ is selected from the group consisting of hydrogen,halogen, lower alkyl groups and lower haloalkyl groups, provided thateither R₁, or R₂ must contain at least one halogen atom. The term“lower,” in the context of this invention, when used to modify “alkyl”or “haloalkyl”, includes C₁ to C₄ alkyls or haloalkyls. Suitablehalogens can include chloro, bromo, iodo and fluoro groups, althoughchloro is preferred. R₁ is preferably a chloromethyl group, and R₂ ispreferably hydrogen. Preferably, the halogenated compounds use in thisinvention are dichloroacetic acid or 2-chloropropionate.

[0022] The halogenated organic compounds of this invention are wellknown compounds which are available from commercial sources.Alternatively, the halogenated organic compounds can be synthesizedusing techniques which are well known in the art to synthetic organicchemists. These compounds are biocompatible and have been found usefulin unrelated therapeutic uses, such as, for instance, the treatment ofsevere lactic acidosis associated with septic shock, P.W. Stacpoole etal., The New England Journal of Medicine, 7, pages 390-396 (1983); andthe treatment of diabetes mellitus and hyperlipoproteinemia, Stacpooleet al., The New England Journal of Medicine, 8, pages 526-530 (1978).

[0023] The halogenated compounds are administered to a subject in apharmaceutical formulation to induce protection against postoperativesurgical adhesion development associated with many common types ofsurgery. Adhesions are a common complication of surgery that involveabnormal union of tissue surfaces, often occurring during the healingprocess of injured cells, tissues and organs. Postoperative surgicaladhesions are a major complication of abdominal, pelvic, gynecologic,cardiothoracic, orthopedic and neuro-surgeries. Adhesions may resultafter a trauma sustained by the body, such as a surgery or a wound, andmay develop in a variety of areas in the body.

[0024] The type and degree of damage caused by adhesions is variable,ranging from life-threatening damage, as in the intestines due toablockage, to extremely disabling damage, as in tendons or spinal cord,to chronic pain and infertility in the pelvic cavity, to the obstructionof further surgery in the pericardium. Adhesions that form in relationto intestinal surgery, e.g., bowel resection, hernia repair, etc., maycause obstruction of the intestine. Adhesions that form near a bonefracture site may reduce or hinder the normal movement in the area ofrepair by restricting the natural movement of tendons over the adjacentbone. Adhesions may also form in the vicinity of nerves and disruptnerve transmissions with a resultant diminution of sensory or motorfunction. Postoperative development of pelvic adhesions remains aserious problem in patients undergoing gynecological surgery and is aprincipal cause of infertility. Postoperative adhesion development cannecessitate difficult reoperations and an increase in injuries duringsubsequent surgeries. In general, the most common causes of pelvicadhesions in women are prior surgery, endometriosis and pelvicinflammatory disease.

[0025] Current clinical methods directed toward reducing the developmentof postoperative surgical adhesions generally rely on placement of afilm or gel directly at the operative site, with the intention ofcreating a physical barrier between surfaces likely to become involvedin adhesion development. These methods remain cumbersome for the surgeonto use.

[0026] Highly concentrated solutions of a number of polymers have beenused to coat the surgical area before and during surgery so as tominimize tissue drying and to act as a cushion to prevent some of themanipulative trauma. Examples of these techniques are described in U.S.Pat. No. 4,819,617 to Goldberg et al. and U.S. Pat. No. 4,886,787 to DeBelder et al. Among the materials used are polyvinylpyrrolidone (PVP),dextrans, hyaluronic acid, carboxymethylcelluloses, and a number ofother polymers such as protein or polypeptide solutions. These materialsdo not entirely eliminate adhesions, but rather reduce the incidence ofadhesion development. The compounds of this invention are believed to besignificantly more effective for adhesion reduction than the barriermaterials of the prior art.

[0027] It has now been discovered, according to the invention, that theadministration of the compounds of the invention, locally orsystemically, can induce protection against postoperative surgicaladhesion development.

[0028] Thus, the compositions of the invention are useful for treatingor preventing adhesions that form at a site and that have potential oractual deleterious effects. These include primary and secondaryadhesions in the following sites: in the abdominal cavity, includingintestine to intestine, and intestine to peritoneum; in the pelviccavity, including adhesions of the uterus, ovaries or fallopian tubes toother structures including each other and the pelvic wall; in tendonsand their support structures, including tendon to pulley or to synovium;in the repair of nerve sheaths; in the repair of the spinal column ordisks; in the pericardium; in the treatment of joints for inflammation,and to prevent pannus formation; in the extraocular muscle, to preventadhesions from limiting the field of vision; and in any situation inwhich adhesions form which can impair the function or cause pain.

[0029] The prevention of postoperative surgical adhesion development ina subject includes prophylactic treatment to prevent adhesiondevelopment following planned surgical procedures, as well as followingemergency operations. In addition to the surgical procedures describedabove, elective surgeries include the following intraabdominalsurgeries: right hemicolectomy; left hemicolectomy; sigmoid colectomy;subtotal colectomy; total colectomy; laparoscopic or opencholecystectomy; gastrectomy; pancreatectomy; splenectomy; liver,pancreas, small bowel, or kidney transplantation; lysis of adhesions;cesarean sections and other pelvic procedures, uterine surgery, etc.Emergency intraabdominal surgeries include those surgeries used tocorrect the following conditions: perforated ulcer (duodenal orgastric); perforated diverticulitis; obstructive diverticulitis; bowelobstruction; perforated appendicitis; blunt abdominal trauma;penetrating abdominal trauma; ruptured abdominal aortic aneurysm,cardiac surgeries, open and endoscopic orthopedic surgeries,neurosurgeries, gynecologic and pelvic surgeries, and surgeries tocorrect wound infections.

[0030] The compounds of the invention are administered in an effectiveamount for inducing protection against postoperative surgical adhesiondevelopment. An effective amount for inducing protection againstpostoperative surgical adhesion development as used herein is thatamount of pharmaceutical composition that will, alone or together withfurther doses or additional therapeutic compounds, inhibit or preventthe development of postoperative surgical adhesions.

[0031] The preparations of the invention when administered “inconjunction with” a surgical procedure, are administered close enough intime with the surgery or trauma that predispose the host to adhesiondevelopment, so that a protective effect against the particular disorderis obtained. The preparations may be administered long before thesurgery, e.g., in the case of elective surgery (i.e., weeks or evenmonths), preferably with booster administrations closer in time to (andeven after) the surgery. Particularly in emergency situations, thepreparations may be administered immediately before (minutes to hours)and/or after the surgery. It is important only that the preparation beadministered close enough in time so as to enhance the subject'sresponse against adhesions, thereby increasing the chances of asuccessful host response and reducing the likelihood of adhesiondevelopment.

[0032] The present invention provides pharmaceutical compositions formedical use, which in some aspects comprise the compounds of theinvention together with one or more pharmaceutically acceptable carriersand optionally other therapeutic ingredients. Thus the invention mayalso include pharmaceutical compositions in combination with ananti-infectious agent such as an antibacterial or anti-viral agent, ananti-inflammatory agent, an antibiotic, or other therapeutic agent, anda pharmaceutically acceptable carrier. The pharmaceutical compositionsuseful in the invention may be delivered separately with the othertherapeutic agents, or in the form of therapeutic cocktails. Atherapeutic cocktail includes a mixture of the pharmaceuticalcomposition of the invention and another therapeutic agent. In thisembodiment, a common administration vehicle (e.g., tablet, implant,injectable solution, etc.) contains both the pharmaceutical compositionand another therapeutic agent. Alternatively, the other therapeutic canbe separately dosed if desired.

[0033] The precise amount of the therapeutic agent used in combinationwith the pharmaceutical compositions of the invention depends upon avariety of factors, including the particular pharmaceutical compositionselected, the dose and dose-timing selected, the mode of administration,the nature of any surgical or medical procedure contemplated, and thecharacteristics of the subject. Where local administration is carriedout, it will be understood that very small amounts may be required(nanograms and possibly picograms). The precise amounts selected can bedetermined without undue experimentation, particularly since a thresholdamount is any amount which will favorably enhance the response.

[0034] Multiple doses of the pharmaceutical compositions of theinvention are also contemplated. For instance, when being administeredin conjunction with a surgical procedure, the compounds of the inventioncan be administered in multiple doses over a three week to one dayperiod preceding surgery. Further, doses may be administered postsurgery as well. Any regimen that prevents or retards the development ofadhesions may be used, although optimum doses and dosing regimens arethose that would not only inhibit the development of adhesion formation,but also would result in protection against adhesion development.Desired time intervals for the delivery of multiple doses of aparticular pharmaceutical composition can be determined by one ofordinary skill in the art employing no more than routineexperimentation.

[0035] The formulations of the invention are administered inpharmaceutically acceptable solutions, which may routinely containpharmaceutically acceptable concentrations of salt, buffering agents,preservatives, compatible carriers, adjuvants, and optionally othertherapeutic ingredients.

[0036] The pharmaceutical composition may be administered per se (neat)or in the form of a pharmaceutically acceptable salt. When used inmedicinal applications, the salts should be pharmaceutically acceptable,but non-pharmaceutically acceptable salts may conveniently be used toprepare pharmaceutically acceptable salts thereof. Such salts include,but are not limited to, those prepared from the following acids:hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic,acetic, salicylic, p-toluene sulphonic, tartaric, citric, methanesulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, andbenzene sulphonic. Also, such salts can be prepared as alkaline metal oralkaline earth salts, such as sodium, potassium or calcium salts of thecarboxylic acid group.

[0037] Suitable buffering agents include: acetic acid or its salt (1-2%w/v); citric acid or its salt (1-3% w/v); boric acid or its salt(0.5-2.5% w/v); succinic acid; and phosphoric acid or its salt (0.8-2%w/v). Suitable preservatives include benzalkonium chloride (0.003-0.03%w/v); chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v) andthimerosal (0.004-0.02% w/v).

[0038] The pharmaceutical compositions of the invention contain aneffective amount of a pharmaceutical composition optionally included ina pharmaceutically acceptable carrier. The term “pharmaceuticallyacceptable carrier” means one or more compatible solid or liquid filler,dilutants or encapsulating substances which are suitable foradministration to a human or other animal. The term “carrier” denotes anorganic or inorganic ingredient, natural or synthetic, with which theactive ingredient is combined to facilitate the application of thecomposition. The components of the pharmaceutical compositions also arecapable of being commingled with the pharmaceutical compositions of thepresent invention, and with each other, in a manner such that there isno interaction which would substantially impair the desiredpharmaceutical efficiency.

[0039] Compositions suitable for parenteral administration convenientlycomprise sterile aqueous preparations, which can be isotonic with theblood of the recipient. Among the acceptable vehicles and solvents arewater, Ringer's solution, and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or di-glycerides. In addition, fattyacids such as oleic acid find use in the preparation of injectables.Carrier formulations suitable for subcutaneous, intramuscular,intraperitoneal or intravenous administrations may be found inRemington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Penn.

[0040] The pharmaceutical compositions useful in the invention may bedelivered in mixtures of more than one pharmaceutical composition. Amixture may consist of several pharmaceutical compositions.

[0041] A variety of administration routes are available. The particularmode selected will depend, of course, upon the particular pharmaceuticalcomposition selected, the particular condition being treated, and thedosage required for therapeutic efficacy. The methods of this invention,generally speaking, may be practiced using any mode of administrationthat is medically acceptable, meaning any mode that produces effectivelevels of an immune response without causing clinically unacceptableadverse effects. Preferred modes of administration include parenteral,injection, infusion, deposition, implantation, anal or vaginalsupposition, oral ingestion, inhalation, topical administration.Injections can be intravenous, intradermal, subcutaneous, intramuscular,or interperitoneal. For example, the pharmaceutical composition can beinjected directly into the surgical site for the prevention ofadhesions. In some embodiments, the injections can be given at multiplelocations. Implantation includes inserting implantable drug deliverysystems, e.g., microspheres, hydrogels, polymeric reservoirs,cholesterol matrixes, polymeric systems, e.g., matrix erosion and/ordiffusion systems and non-polymeric systems, e.g., compressed, fused, orpartially-fused pellets. Inhalation includes administering thepharmaceutical composition with an aerosol in an inhaler, either aloneor attached to a carrier that can be absorbed. For systemicadministration, it may be preferred that the pharmaceutical compositionis encapsulated in liposomes. The term “parenteral” includessubcutaneous injections, intravenous, intramuscular, intraperitoneal,and intrasternal injection or infusion techniques.

[0042] In certain preferred embodiments of the invention, theadministration can be designed so as to result in sequential exposure tothe pharmaceutical composition over some period of time, e.g., hours,days, weeks, months or years. This can be accomplished by repeatedadministrations of the pharmaceutical composition, by one of the methodsdescribed above, or alternatively, by a sustained-release deliverysystem in which the pharmaceutical composition is delivered to thesubject for a prolonged period without repeated administrations. Bysustained-release delivery system, it is meant that total release of thepharmaceutical composition does not occur immediately uponadministration, but rather is delayed for some period of time. Releasecan occur in bursts or it can occur gradually and continuously.Administration of such a system can be, e.g., by long-lasting oraldosage forms, bolus injections, transdermal patches, and subcutaneousimplants.

[0043] Examples of systems in which release occurs in bursts includes,e.g., systems in which the pharmaceutical composition is entrapped inliposomes which are encapsulated in a polymer matrix, the liposomesbeing sensitive to specific stimuli, e.g., temperature, pH, light or adegrading enzyme and systems in which the pharmaceutical composition isencapsulated by an ionically-coated microcapsule with a microcapsulecore degrading enzyme. Examples of systems in which release of thepharmaceutical composition is gradual and continuous include, e.g.,erosional systems in which the pharmaceutical, composition is containedin a form within a matrix, and effusional systems in which thepharmaceutical composition permeates at a controlled rate, e.g., througha polymer. Such sustained release systems can be e.g., in the form ofpellets, or capsules.

[0044] In one particular embodiment, the preferred sustained releasedevice is a biocompatible microparticle or microencapsulated product orimplant that is suitable for implantation or administration to themammalian recipient. Exemplary bioerodible implants that are useful inaccordance with this method are described in PCT Internationalapplication no. PCT/US/03307 (Publication No. WO 95/24929, entitled“Polymeric Gene Delivery System.”) The polymeric matrix preferably is inthe form of a microparticle such as a microsphere (wherein thepharmaceutical composition is dispersed throughout a solid polymericmatrix) or a microcapsule (wherein the pharmaceutical composition isstored in the core of a polymeric shell). Other forms of the polymericmatrix for containing the pharmaceutical composition include films,coatings, gels, implants, and stents. The size and composition of thepolymeric matrix device is selected to result in favorable releasekinetics in the tissue into which the matrix is introduced. The size ofthe polymeric matrix further is selected according to the method ofdelivery which is to be used, typically injection into a tissue. Thepolymeric matrix composition can be selected to have both favorabledegradation rates and also to be formed of a material which isbioadhesive, to further increase the effectiveness of transfer when thematrix is administered to a mucosal surface. The matrix composition alsocan be selected not to degrade, but rather to release by diffusion overan extended period of time. The biocompatible microsphere may besuitable for oral delivery. Such microspheres are disclosed inChickering et al., Biotech. And Bioeng., (1996) 52:96-101 and Mathiowitzet al., Nature, (1997) 386:410-414 and PCT Patent Application No.WO97/03702.

[0045] Both non-biodegradable and biodegradable polymeric matrices canbe used to deliver the pharmaceutical compositions to the subject.Biodegradable matrices are preferred. Such polymers may be natural orsynthetic polymers. The polymer is selected based on the period of timeover which release is desired, generally in the order of a few hours toa year or longer. Typically, release over a period ranging from betweena few hours and three to twelve months is most desirable. The polymeroptionally is in the form of a hydrogel that can absorb up to about 90%of its weight in water, and further optionally is cross-linked withmulti-valent ions or other polymers.

[0046] Bioadhesive polymers of particular interest include bioerodiblehydrogels described by H. S. Sawhney, C. P. Pathak and J. A. Hubell inMacromolecules, (1993) 26:581-587, the teachings of which areincorporated herein by reference, casein, gelatin, glutin,polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methylmethacrylates), poly(ethyl methacrylates), poly(butylmethacrylate),polyhyaluronic acids, poly(isobutyl Miiiethaerylate),poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(laurylmethacrylate), poly(phenyl methacrylate), poly(methyl acrylate),poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecylacrylate).

[0047] Other sustained release delivery systems useful according to theinvention include, but are not limited to, fatty acids and a medicinalpump. Preferably the fatty acids are C₉-C₂₀ fatty acids.

[0048] The compositions may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Such methods include the step of bringing the pharmaceuticalcomposition into association with a carrier which constitutes one ormore accessory ingredients. In general, the compositions are prepared byuniformly and intimately bringing the pharmaceutical composition intoassociation with a liquid carrier, a finely divided solid carrier, orboth, and then, if necessary, shaping the product. The pharmaceuticalcomposition may be stored in a lyophilized condition.

[0049] The pharmaceutical compositions can be suspended in a liquid,e.g., in dissolved form or colloidal form. The liquid can be a solvent,partial solvent, or non-solvent. In many cases, water or an organicliquid can be used.

[0050] The pharmaceutical compositions are administered to the subjectin a therapeutically-effective amount. By therapeutically-effectiveamount it is meant that amount which is capable of at least partiallypreventing, reversing, reducing, decreasing, ameliorating, or otherwisesuppressing adhesions. A therapeutically-effective amount can bedetermined on an individual basis and is based, at least in part, onconsideration of the age, sex, size, and health of the subject; the typeof pharmaceutical composition used, the type of delivery system used;the time of administration; and whether a single, multiple, orcontrolled-release dose regimen is employed. A therapeutically-effectiveamount can be determined by one of ordinary skill in the art employingsuch factors and using no more than routine experimentation.

[0051] The dosage concentration of the pharmaceutical compositionactually administered is dependent, at least in part, upon the finalconcentration of the pharmaceutical composition that is desired at thesite of action, the method of administration, the efficacy of theparticular pharmaceutical composition, the longevity of the particularpharmaceutical composition, and the timing of administration.Preferably, the dosage form is such that it does not substantiallydeleteriously affect the subject. The dosage can be determined by one ofordinary skill in the art employing such factors and using no more thanroutine experimentation.

[0052] The term “subject,” as used herein, means a human or non-humanmammal, including but not limited to, a dog, cat, horse, cow, pig,sheep, goat, primate, rat, and mouse.

EXAMPLES

[0053] An animal adhesion study to evaluate the effectiveness of thepharmaceutical compositions described previously is conducted using astandardized animal model, such as a model of cecal abrasion in the rator an oravian bisection in the rabbit.

[0054] The animals undergo lesioning by a surgeon unaware of groupassignment, with necropsy performed one to two weeks later as isstandard for that particular animal model.

[0055] The animals are randomized in a placebo control group and a groupusing dichloroacetic acid. The treatment begins preoperatively, andcontinues for five days after surgery. Dichloroacetic acid isadministered by intravenous injection, or by slow release from adelivery agent, and is left in the peritoneal cavity following surgery.The maintenance of adequate amounts of dichloroacetic acid can bemonitored by the measurement of serum alanine and lactate, which isreduced in the presence of dichloroacetic acid. Necropsy is performed onthe animals, and adhesions are scored. Studies are completed on a totalof 30 animals in each group in at least three settings.

[0056] Similarly, cell cultures using human mesothelial cells or humanfibroblasts are cultured under hypoxic conditions in the presence andabsence of dichloroacetic acid. The production of inflammatory cytokinesand growth factors is measured, and found to be reduced in the presenceof dichloroacetic acid. These growth factors, such as IL-1 and TGF-β,are believed to be associated with adhesion development.

[0057] Each of the foregoing patents, patent applications and referencesthat are recited in this application are herein incorporated in theirentirety by reference. Having described the presently preferredembodiments, and in accordance with the present invention, it isbelieved that other modifications, variations and changes will besuggested to those skilled in the art in view of the teachings set forthherein. It is, therefore, to be understood that all such variations,modifications, and changes are believed to fall within the scope of thepresent invention as defined by the appended claims.

What is claimed is:
 1. A method for preventing or reducing thedevelopment of surgical adhesions in a subject comprising treating asubject at risk of developing such adhesions with an effective amount ofa therapeutic formulation containing, as an active ingredient, ahalogenated organic compound of formula CR₁OOR₂, wherein R₁ is a loweralkyl or a lower haloalkyl, and wherein R₂ is selected from the groupconsisting of hydrogen, halogen, lower alkyl and lower haloalkyl,provided that either R₁ or R₂ must contain at least one halogen.
 2. Themethod of claim 1 wherein the halogenated organic compound is an aceticacid derivative.
 3. The method of claim 2 wherein the halogenatedorganic compound is dichloroacetic acid.
 4. The method of claim 2wherein the halogenated organic compound is 2-chloropropionate.
 5. Themethod of claim 1 wherein the halogen is chlorine.
 6. The method ofclaim 1 wherein the lower alkyl is methyl and the lower haloalkyl ishalomethyl.
 7. A pharmaceutical composition for preventing or retardingthe development of surgical adhesions comprising the compound of claims1, 2, 3, 4, 5 or 6 and a pharmaceutically acceptable carrier.
 8. Thepharmaceutical composition of claim 7 which is administered to a patientwho will undergo a surgical procedure.
 9. The pharmaceutical compositionof claim 8 wherein the surgical procedure is abdominal surgery.
 10. Thepharmaceutical composition of claim 8 wherein the pharmaceuticalcomposition is administered to the patient prior to or during surgery,and for a period of up to five days following surgery.